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Cataract is a leading ocular disease causing global blindness. The mechanism of cataractogenesis has not been well defined. Here, we demonstrate that the heat shock protein 90ß (HSP90ß) plays a fundamental role in suppressing cataractogenesis. HSP90ß is the most dominant HSP in normal lens, and its constitutive high level of expression is largely derived from regulation by Sp1 family transcription factors. More importantly, HSP90ß is significantly down-regulated in human cataract patients and in aging mouse lenses, whereas HSP90ß silencing in zebrafish causes cataractogenesis, which can only be rescued by itself but not other HSP90 genes. Mechanistically, HSP90ß can directly interact with CHMP4B, a newly-found client protein involved in control of cytokinesis. HSP90ß silencing causes upregulation of CHMP4B and another client protein, the tumor suppressor p53. CHMP4B upregulation or overexpression induces excessive division of lens epithelial cells without proper differentiation. As a result, these cells were triggered to undergo apoptosis due to activation of the p53/Bak-Bim pathway, leading to cataractogenesis and microphthalmia. Silence of both HSP90ß and CHMP4B restored normal phenotype of zebrafish eye. Together, our results reveal that HSP90ß is a critical inhibitor of cataractogenesis through negative regulation of CHMP4B and the p53-Bak/Bim pathway.
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Catarata , Proteínas HSP90 de Choque Térmico , Proteína p53 Supresora de Tumor , Animales , Humanos , Ratones , Envejecimiento/genética , Catarata/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Cuerpos Multivesiculares/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
In the realm of organic synthesis, the catalytic and stereoselective formation of C-glycosidic bonds is a pivotal process, bridging carbohydrates with aglycones. However, the inherent chirality of the saccharide scaffold often has a substantial impact on the stereoinduction imposed by a chiral ligand. In this study, we have established an unprecedented zirconaaziridine-mediated asymmetric nickel catalysis, enabling the diastereoselective coupling of bench-stable glycosyl phosphates with a range of (hetero)aromatic and glycal iodides as feasible coupling electrophiles. Our developed method showcases a broad scope and a high tolerance for various functional groups. More importantly, precise stereocontrol toward both anomeric configurations of forming C(sp2)-glycosides can be realized by simply utilizing the popular chiral bioxazoline (biOx) ligands in this reductive Ni catalysis. Regarding the operating mechanism, both experimental and computational studies support the occurrence of a redox transmetalation process, leading to the formation of a transient, bimetallic Ni-Zr species that acts as a potent and efficient single-electron reductant in the catalytic process.
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Denoising is a necessary step in image analysis to extract weak signals, especially those hardly identified by the naked eye. Unlike the data-driven deep-learning denoising algorithms relying on a clean image as the reference, Noise2Noise (N2N) was able to denoise the noise image, providing sufficiently noise images with the same subject but randomly distributed noise. Further, by introducing data augmentation to create a big data set and regularization to prevent model overfitting, zero-shot N2N-based denoising was proposed in which only a single noisy image was needed. Although various N2N-based denoising algorithms have been developed with high performance, their complicated black box operation prevented the lightweight. Therefore, to reveal the working function of the zero-shot N2N-based algorithm, we proposed a lightweight Peak2Peak algorithm (P2P) and qualitatively and quantitatively analyzed its denoising behavior on the 1D spectrum and 2D image. We found that the high-performance denoising originates from the trade-off balance between the loss function and regularization in the denoising module, where regularization is the switch of denoising. Meanwhile, the signal extraction is mainly from the self-supervised characteristic learning in the data augmentation module. Further, the lightweight P2P improved the denoising speed by at least ten times but with little performance loss, compared with that of the current N2N-based algorithms. In general, the visualization of P2P provides a reference for revealing the working function of zero-shot N2N-based algorithms, which would pave the way for the application of these algorithms toward real-time (in situ, in vivo, and operando) research improving both temporal and spatial resolutions. The P2P is open-source at https://github.com/3331822w/Peak2Peakand will be accessible online access at https://ramancloud.xmu.edu.cn/tutorial.
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BACKGROUND AND AIMS: The liver has the unique ability of regeneration, which is extremely important for restoring homeostasis after liver injury. Although clinical observations have revealed an association between psychological stress and the liver, whether stress has a causal influence on the liver regeneration remains markedly less defined. APPROACH AND RESULTS: Rearing rodents in an enriched environment (EE) can induce eustress or positive psychological stress. Herein, EE-induced eustress was found to significantly enhance the ability of liver regeneration after partial hepatectomy or carbon tetrachloride-induced liver injury based on the more rapid restoration of liver/body weight ratio and the significantly increased number of proliferating hepatocytes in EE mice. Mechanistically, the cytokine array revealed that IL-22 was markedly increased in the regenerating liver in response to EE. Blockade of IL-22 signaling abrogated the enhanced liver regeneration induced by EE. Group 1 innate lymphoid cells (ILCs), including type 1 ILCs (ILC1s), have been identified as the major sources of IL-22 in the regenerating liver. EE housing led to a rapid accumulation of hepatic ILC1s after partial hepatectomy and the EE-induced enhancement of liver regeneration and elevation of IL-22 was nearly eliminated in ILC1-deficient Tbx21-/- mice. Chemical sympathectomy or blockade of ß-adrenergic signaling also abolished the effect of EE on ILC1s and attenuated the enhanced liver regeneration of EE-housed mice. CONCLUSION: The study findings support the brain-liver axis and suggest that environment-induced eustress promotes liver regeneration through the sympathetic nerve/ILC1/IL-22 axis.
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Inmunidad Innata , Regeneración Hepática , Ratones , Animales , Regeneración Hepática/fisiología , Linfocitos , Interleucinas , Hepatectomía , Hígado , Hepatocitos/fisiología , Ratones Endogámicos C57BL , Interleucina-22RESUMEN
The microwave and millimeter-wave (MMW) imaging technology is gaining increasing interest for food inspection. It allows for noninvasive, contactless, and fast scanning capabilities, while being cost-efficient and safe to human. This review paper introduces the fundamentals in the interaction of electromagnetic wave with food materials and the current MMW sensing and imaging systems used for foods. Then we present emerging technologies in MMW imaging for inspecting food quality and safety, aiming to meet the modern food industry's demand. According to the most recent technological advancements, it is expected that high-performance antenna, ultrawide bandwidth signal generation, nano-scale semiconductor technologies, radio frequency identification with inductance-capacitance resonator, and machine learning could significantly enhance the capabilities of MMW imaging systems for food inspection.
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Chronic pain is a serious problem that affects billions of people worldwide, but current analgesic drugs limit their use in chronic pain management due to their respective side effects. As a first-line clinical drug for chronic pain, COX-2 selective inhibitors can relieve mild to moderate pain, but they also have some problems. The most prominent one is that their analgesic intensity is not enough, and they cannot well meet the treatment needs of chronic pain. Therefore, there is an urgent need to develop COX-2 inhibitors with stronger analgesic intensity. In this article, we used virtual screening method to screen out the structurally novel COX-2 inhibitor for chronic pain management, and conducted a preliminary study on its mechanism of action using molecular dynamics simulation.
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Dolor Crónico , Inhibidores de la Ciclooxigenasa 2 , Humanos , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Antiinflamatorios no Esteroideos/farmacología , Dolor Crónico/tratamiento farmacológico , Analgésicos/farmacología , Analgésicos/uso terapéutico , FuranosRESUMEN
Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c, 18d, and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b, 15c, 15e, and 15h having a shorter duration at 272.7 nmol/kg. The structure-activity and configuration-activity relationships of these derivatives and 29a's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA.
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Diseño de Fármacos , Isoquinolinas , Bloqueantes Neuromusculares , Bloqueantes Neuromusculares/farmacología , Bloqueantes Neuromusculares/síntesis química , Bloqueantes Neuromusculares/química , Relación Estructura-Actividad , Animales , Isoquinolinas/química , Isoquinolinas/farmacología , Isoquinolinas/síntesis química , Conejos , Receptores Nicotínicos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Dosis-Respuesta a Droga , Mivacurio , Atracurio/análogos & derivados , Atracurio/farmacología , Atracurio/síntesis química , Atracurio/químicaRESUMEN
The NaV1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments.
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Amidas , Neuralgia , Compuestos Organotiofosforados , Humanos , Amidas/química , Analgésicos/farmacología , Analgésicos/uso terapéutico , Canal de Sodio Activado por Voltaje NAV1.7 , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Piridonas/química , Piridonas/farmacologíaRESUMEN
Visuospatial attention (VSA) is a cognitive function that enables athletes, particularly those engaged in open-skill sports, to allocate attentional resources efficiently to the appropriate target and in the appropriate direction. Studies have indicated that expert players exhibit superior cognitive performance to that of novices. However, no study has investigated differences in VSA performance among elite, expert, and intermediate badminton players or the potential neurophysiological mechanisms underlying such differences. Accordingly, the present study explored neuropsychological and neurophysiological parameters during VSA tasks among badminton players of varying competitive levels. The study included 54 participants and divided them into three groups according to their competition records: elite (n = 18), expert (n = 18), and intermediate (n = 18). Their neuropsychological performance and brain event-related potentials (ERPs) during the Posner cueing paradigm were collected. Although the three groups did not differ in their accuracy rates, ERP N2 amplitudes, or N2 or P3 latencies, the elite and expert groups exhibited notably faster reaction times and more pronounced P3 amplitudes than did the intermediate group during the cognitive task. However, we did not observe these between-group differences when we controlled for the covariate training years. Additionally, the elite and expert groups exhibited comparable neurocognitive performance. These findings indicate that badminton players' competitive levels influence their VSA. However, the beneficial effects on neuropsychological and neurophysiological performance could stabilize after a certain level of badminton competence is reached. Year of training could also be a major factor influencing badminton players' neurocognitive performance in VSA tasks.
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Atención , Electroencefalografía , Potenciales Evocados , Deportes de Raqueta , Percepción Espacial , Humanos , Atención/fisiología , Masculino , Deportes de Raqueta/fisiología , Adulto Joven , Potenciales Evocados/fisiología , Percepción Espacial/fisiología , Adulto , Femenino , Percepción Visual/fisiología , Tiempo de Reacción/fisiología , Desempeño Psicomotor/fisiología , Adolescente , Conducta Competitiva/fisiología , Rendimiento Atlético/fisiologíaRESUMEN
Ten new (1-10) and nine known (11-19) austocystins, along with four known anthraquinones (20-23), were isolated from the culture of Aspergillus ustus NRRL 5856 by bioactivity-guided fractionation. The structures of the new compounds were elucidated by spectroscopic data analysis, X-ray crystallographic study, the modified Mosher's method, [Rh2(OCOCF3)4]-induced ECD spectral analysis, and comparison of the experimental ECD spectra with those of the similar analogues. Compounds 1-8 represent the first examples of austocystins with a C-4' oxygenated substitution. The absolute configuration of 1â³-hydroxy austocystin D (11) was determined by single-crystal X-ray diffraction and consideration of its biosynthetic origin. Compounds 5, 9, and 11 exhibited significant inhibitory effects against the proliferation of ConA-induced T cells with IC50 values of 1.1, 1.0, and 0.93 µM, respectively. Furthermore, these compounds suppressed the expression of IL-6 in a dose-dependent manner. Compounds 10-12 and 14 showed pronounced cytotoxicities against MCF-7 with IC50 values of 3.9, 1.3, 0.46, and 2.3 µM, respectively.
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Aspergillus , Inmunosupresores , Aspergillus/química , Humanos , Inmunosupresores/farmacología , Inmunosupresores/química , Inmunosupresores/aislamiento & purificación , Estructura Molecular , Cristalografía por Rayos X , Interleucina-6/metabolismo , Antraquinonas/farmacología , Antraquinonas/química , Animales , Ensayos de Selección de Medicamentos Antitumorales , Linfocitos T/efectos de los fármacos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacosRESUMEN
Among the numerous complications of diabetes mellitus, diabetic wounds seriously affect patients' quality of life and result in considerable psychological distress. Promoting blood vessel regeneration in wounds is a crucial step in wound healing. Lonicerin (LCR), a bioactive compound found in plants of the Lonicera japonica species and other honeysuckle plants, exhibits anti-inflammatory and antioxidant activities, and it recently has been found to alleviate ulcerative colitis by enhancing autophagy. In this study we investigated the efficacy of LCR in treatment of diabetic wounds and the underlying mechanisms. By comparing the single-cell transcriptomic data from healing and non-healing states in diabetic foot ulcers (DFU) of 5 patients, we found that autophagy and SIRT signaling activation played a crucial role in mitigating inflammation and oxidative stress, and promoting cell survival in wound healing processes. In TBHP-treated human umbilical vein endothelial cells (HUVECs), we showed that LCR alleviated cell apoptosis, and enhanced the cell viability, migration and angiogenesis. Furthermore, we demonstrated that LCR treatment dose-dependently promoted autophagy in TBHP-treated HUVECs by upregulating Sirt1 expression, and exerted its anti-apoptotic effect through the Sirt1-autophagy axis. Knockdown of Sirt1 significantly decreased the level of autophagy, and mitigated the anti-apoptotic effect of LCR. In a STZ-induced diabetic rat model, administration of LCR significantly promoted wound healing, which was significantly attenuated by Sirt1 knockdown. This study highlights the potential of LCR as a therapeutic agent for the treatment of diabetic wounds and provides insights into the molecular mechanisms underlying its effects.
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Diabetes Mellitus Experimental , Luteolina , Cicatrización de Heridas , Animales , Humanos , Ratas , Autofagia/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Luteolina/farmacología , Luteolina/uso terapéutico , Calidad de Vida , Sirtuina 1/genética , Sirtuina 1/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
BACKGROUND: The incidence of young patients diagnosed with hepatocellular carcinoma (HCC) is projected to rise. This study aimed to investigate the distinctive characteristics of adolescent and young adult (AYA) patients with HCC and identify the risk factors that impact their survival. METHODS: This study included 1005 AYA patients and 55,435 older adult (OA) patients with HCC, using data from the Surveillance, Epidemiology, and End Results database. Propensity score matching was used to adjust for baseline differences in patient characteristics. The Kaplan-Meier curve and log-rank test are utilized to compare the overall survival between the two groups. The Cox proportional hazards regression model was used for subgroup analysis to identify risk factors for overall survival in AYA patients. RESULTS: AYA patients exhibited a higher proportion of advanced clinical stage (49.15% vs 37.57%, P < 0.001) and fibrolamellar hepatocellular carcinoma (14.13% vs 0.09%, P < 0.001), but a lower incidence of alpha-fetoprotein positivity (32.04% vs 45.32%, P < 0.001) and cirrhosis (8.86% vs 18.32%, P < 0.001). The subgroup analysis results indicated that AYA patients had a more favorable prognosis than OA patients in most subgroups. Undifferentiated carcinoma emerged as the predominant risk factor for AYA patients (Hazard Ratio [HR], 6.08 [2.53-14.62]), whereas partial hepatectomy was determined to be the most advantageous factor (HR, 0.29 [0.23-0.37]). CONCLUSIONS: AYA patients with HCC exhibit more aggressive characteristics but demonstrate a better prognosis compared to the OA group, necessitating personalized surveillance and treatment.
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To date, over 200 families with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and over 600 families with Birt-Hogg-Dubé (BHD) syndrome have been reported, with low incidence. Here, we describe a patient with suspected rare HLRCC complicated by BHD syndrome. The proband (II1) had characteristic cutaneous leiomyoma-like protrusions on the neck and back, a left renal mass and multiple right renal, liver and bilateral lung cysts. Three family members (I1, II2, II3) had a history of renal cancer and several of the aforementioned clinical features. Two family members (II1, II3) diagnosed with fumarate hydratase (FH)-deficient papillary RCC via pathological biopsy carried two heterozygous variants: FH (NM_000143.3) missense mutation c.1189G>A (p.Gly397Arg) and FLCN (NM_144997.5) frameshift mutation c.1579_1580insA (p.Arg527Glnfs*75). No family member carrying a single variant had renal tumours. In HEK293T cells transfected with mutant vectors, mRNA and protein expression after FLCN p.Arg527Glnfs*75 and FH p.Gly397Arg mutations were significantly lower than those in wild-type (WT) cells. Cell immunofluorescence showed altered protein localisation and reduced protein expression after FLCN p.Arg527Glnfs*75 mutation. The FH WT was uniformly distributed in the cytoplasm, whereas FH protein expression was reduced after the p.Gly397Arg mutation and scattered sporadically with altered cell localisation. Patients with two variants may have a significantly increased penetrance of RCC.
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Síndrome de Birt-Hogg-Dubé , Carcinoma de Células Renales , Neoplasias Renales , Leiomiomatosis , Humanos , Síndrome de Birt-Hogg-Dubé/complicaciones , Síndrome de Birt-Hogg-Dubé/genética , Carcinoma de Células Renales/complicaciones , Carcinoma de Células Renales/genética , Células HEK293 , Neoplasias Renales/complicaciones , Neoplasias Renales/genética , Leiomiomatosis/complicaciones , Leiomiomatosis/genética , FenotipoRESUMEN
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, is known to cause teratogenesis. Environmental exposure of BaP has led to wide public concerns due to their potential risk of reproductive toxicity. However, the exact mechanism is still not clear. We aimed to explore the alterations of oxidative stress and DNA hydroxymethylation during BaP-impaired reproductive function. BALB/c mice were intragastrically administered with different doses of BaP (0.01, 0.1, and 1 mg/kg/day, once a day), while control mice were administered with corn coil. Then, the reproductive function, alterations of oxidative stress, DNA methylation, and DNA hydroxymethylation of testis tissues were evaluated. We found that BaP caused obvious histopathological damages of testis tissues. As for sperm parameters after BaP administration, testis weight and the rate of teratosperm were increased, as well as sperm count and motility were decreased. In mechanism, BaP upregulated HO-1 and MDA levels and downregulated SOD and CAT activity and GSH content in testis tissues, indicating that oxidative stress was induced by BaP. Furthermore, a significant induction of hydroxymethylation and inhibition of methylation were observed in testis tissues after BaP exposure. Collectively, BaP-induced oxidative stress and hydroxymethylation were involved in impairing reproductive function, which may be the mechanism of the male infertility.
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The treadmill exercise test (TET) serves as a non-invasive method for the diagnosis of coronary artery disease (CAD). Despite its widespread use, TET reports are susceptible to external influences, heightening the risk of misdiagnosis and underdiagnosis. In this paper, we propose a novel automatic CAD diagnosis approach. The proposed approach introduces a customized preprocessing method to obtain clear electrocardiograms (ECGs) from individual TET reports. Additionally, it presents TETDiaNet, a novel neural network designed to explore the temporal relationships within TET ECGs. Central to TETDiaNet is the TETDia block, which mimics clinicians' diagnostic processes to extract essential diagnostic information. This block encompasses an intra-state contextual learning module and an inter-state contextual learning module, modeling the temporal relationships within a single state and between states, respectively. These two modules help the TETDia block to capture effective diagnosis information by exploring the temporal relationships within TET ECGs. Furthermore, we establish a new TET dataset named TET4CAD for CAD diagnosis. It contains simplified TET reports for 192 CAD patients and 224 non-CAD patients, and each patient undergoes coronary angiography for labeling. Experimental results on TET4CAD underscore the superior performance of the proposed approach, highlighting the discriminative value of the temporal relationships within TET ECGs for CAD diagnosis.
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Enfermedad de la Arteria Coronaria , Electrocardiografía , Prueba de Esfuerzo , Redes Neurales de la Computación , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico , Prueba de Esfuerzo/métodos , Electrocardiografía/métodos , Masculino , Algoritmos , FemeninoRESUMEN
Objectives: Autologous blood transfusion techniques are well applied in surgery, but the red blood cells (RBCs) collected during laparoscopic surgery may forfeit their ability to oxygenate. O3 is a potent oxidation gas. This study investigates whether O3 could improve the oxygen-carrying capacity of RBCs, reduce inflammatory reactions, and offer organ protection. Methods: We established a hemorrhagic shock model in rabbits, and simulated CO2 pneumoperitoneum and O3 were applied before autologous blood transfusion. Perioperative mean arterial pressure and arterial blood gas were recorded, blood gas and RBC morphology of collected blood were analyzed, plasma IL-6, ALT, AST, CRE, and lung histopathology POD0 and POD3 were tested, as well as postoperative survival quality. Results: Autologous blood that underwent simulated CO2 pneumoperitoneum had a lower pH and SaO2 and a higher PaCO2 than the control group. After O3 treatment, PaO2 and SaO2 increased significantly, with unchanged pH values and PaCO2. RBCs in autologous blood were drastically deformed after CO2 conditioning and then reversed to normal by O3 treatment. Rabbits that received CO2-conditioned autologous blood had a compromised survival quality after surgery, higher plasma IL-6 levels, higher lung injury scores on POD0, higher ALT and AST levels on POD3, and O3 treatment alleviated these adverse outcomes. Conclusion: O3 can restore RBC function, significantly improve blood oxygenation under simulated CO2 pneumoperitoneum, offer organ protection, and improve the postoperative survival quality in the rabbit hemorrhage shock model.
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OBJECTIVES: To investigate the neurodevelopmental characteristics of children with autism spectrum disorder (ASD), analyze the correlation between neurodevelopmental indicators and cerebral blood flow (CBF), and explore the potential mechanisms of neurodevelopment in ASD children. METHODS: A retrospective study was conducted on 145 children aged 2-6 years with newly-diagnosed ASD. Scores from the Gesell Developmental Diagnosis Scale and the Autism Behavior Checklist (ABC) and CBF results were collected to compare gender differences in the development of children with ASD and analyze the correlation between CBF and neurodevelopmental indicators. RESULTS: Fine motor and personal-social development quotient in boys with ASD were lower than those in girls with ASD (P<0.05). Gross motor development quotient in ASD children was negatively correlated with CBF in the left frontal lobe (r=-0.200, P=0.016), right frontal lobe (r=-0.279, P=0.001), left parietal lobe (r=-0.208, P=0.012), and right parietal lobe (r=-0.187, P=0.025). The total ABC score was positively correlated with CBF in the left amygdala (r=0.295, P<0.001). CONCLUSIONS: Early intervention training should pay attention to gender and developmental structural characteristics for precise intervention in ASD children. CBF has the potential to become a biological marker for assessing the severity of ASD.
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Trastorno del Espectro Autista , Circulación Cerebrovascular , Humanos , Masculino , Trastorno del Espectro Autista/fisiopatología , Femenino , Preescolar , Niño , Estudios Retrospectivos , Desarrollo InfantilRESUMEN
OBJECTIVES: The protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown. METHODS: We applied empagliflozin treatment to lupus-prone MRL/lpr mice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms. RESULTS: In MRL/lpr mice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/lpr mice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors. CONCLUSION: This study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.
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Diabetes Mellitus Tipo 2 , Nefritis Lúpica , Podocitos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Ratones , Autofagia , Inmunoglobulina G/metabolismo , Inflamación/patología , Riñón/patología , Nefritis Lúpica/tratamiento farmacológico , Ratones Endogámicos MRL lpr , Podocitos/patología , Proteinuria , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , HumanosRESUMEN
The image reconstruction for Fourier-domain optical coherence tomography (FD-OCT) could be achieved by iterative methods, which offer a more accurate estimation than the traditional inverse discrete Fourier transform (IDFT) reconstruction. However, the existing iterative methods are mostly A-line-based and are developed on CPU, which causes slow reconstruction. Besides, A-line-based reconstruction makes the iterative methods incompatible with most existing image-level image processing techniques. In this paper, we proposed an iterative method that enables B-scan-based OCT image reconstruction, which has three major advantages: (1) Large-scale parallelism of the OCT dataset is achieved by using GPU acceleration. (2) A novel image-level cross-domain regularizer was developed, such that the image processing could be performed simultaneously during the image reconstruction; an enhanced image could be directly generated from the OCT interferogram. (3) The scalability of the proposed method was demonstrated for 3D OCT image reconstruction. Compared with the state-of-the-art (SOTA) iterative approaches, the proposed method achieves higher image quality with reduced computational time by orders of magnitude. To further show the image enhancement ability, a comparison was conducted between the proposed method and the conventional workflow, in which an IDFT reconstructed OCT image is later processed by a total variation-regularized denoising algorithm. The proposed method can achieve a better performance evaluated by metrics such as signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), while the speed is improved by more than 30 times. Real-time image reconstruction at more than 20 B-scans per second was realized with a frame size of 4096 (axial) × 1000 (lateral), which showcases the great potential of the proposed method in real-world applications.
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A stable speckle pattern is generated when a coherent beam illuminates a stationary scattering medium that contains numerous scatterers with fixed positions. To date, there has been no valid method to the best of our knowledge for calculating the speckle pattern of a macro medium with a large number of scatterers. Here, a new method based on possible path sampling with corresponding weights and coherent superposition is presented for the simulation of optical field propagation in a scattering medium and output speckle patterns. In this method, a photon is launched onto a medium with fixed scatterers. It propagates in one direction; upon collision with a scatterer, its direction is updated. The procedure is repeated until it exits the medium. A sampled path is obtained in this manner. By repeatedly launching photons, numerous independent optical paths can be sampled. A speckle pattern, corresponding to the probability density of the photon, is formed by the coherent superposition of sufficiently sampled path lengths ending on a receiving screen. This method can be used in sophisticated studies of the influences of medium parameters, motion of scatterers, sample distortions on speckle distributions, and morphological appearances. It can be used for micro-examination of optical fields in scattering media and may inspire new methods and techniques for non-invasive precision detection and diagnosis of scattering media.